1. Field of the Invention
This invention relates to a new molecular structure which is a complex of the known prostaglandin PGE, derivative, rioprostil, and polyvinylpyrrolidone (PVP) which is particularly useful as an improved dosage form for tablets and capsules.
Rioprostil is the United States Adapted Name (USAN generic name) for the compound which has also been referred to by the following names and code numbers:
(1) 1,11,16-trihydroxy-16-methyl-,(11.alpha.,13E)-prost-13-en-9-one; (2) (2R,3R,4R)-4-Hydroxy-2-(7-hydroxyheptyl)-3-[(E)-(4RS)-4-hydroxy-4-methyl-1 -octenyl)]cyclopentanone; (3) CAS-77287-05-9; (4) TR-4698; (5) ORF-15927 PA0 "The present invention furthermore relates to a process for the preparation of stable prostaglandin formulations in which the prostaglandin is applied in dissolved form to crosspovidone and is then dried. The present invention moreover relates to medicaments containing prostaglandins adsorbed onto crospovidone and to the use of prostaglandins, or derivatives thereof, adsorbed onto crosspovidone in or as medicaments and for combating diseases, in particular for combating gastrointestinal ulcers, hypertension, bronchial asthma and thromboses, and for inducing labor and/or abortions in mammals. PA0 In the context of the present invention, crosspovidones are understood as meaning polyvinylpyrrolidone crosslinked by further polymerization, especially a water-insoluble polyvinylpyrrolidone of this type. In the context of the present invention, crosspovidones which meet the specification of NF XV (National Formulary, 15 Edition, Official Nov. 1, 1981, the United States Pharmacoperial Convention, Inc.) are preferred."
Rioprostil exists, as do most prostaglandins, as an oil at room temperature. This oil is particularly viscous and was found on occasion to cause irritation to mucous membranes during routine handling. Both of these factors contribute to making rioprostil uncommonly difficult to handle. In addition, rioprostil was determined to have poor aqueous solubility and to be heat labile at room temperature. Rioprostil is a very potent medicinal substance and therefore requires a very low dosage strength. This posed a problem in that extreme manufacturing procedures would be required to insure content uniformity of the viscous oil from dose to dose in the desired tablet or capsule product. The instant invention solved these problems.
2. Description of The Prior Art
Rioprostil and its method of preparation are disclosed in U.S. Pat. No. 4,132,738 and U.S. Pat. No. 4,370,348. The latter patent teaches the use of rioprostil in a method of inducing cytoprotection in mammals, in a method of preventing gastrointestinal lesions, and, in a method of treating gastrointestinal lesions in mammals. The dosage level of rioprostil to be used in such disclosed methods of treatment is 2-200 micrograms, and the rioprostil may be administered in oral dosage form as a powder, capsule or tablet, using a pharmaceutical carrier such as starches, sugars, diluents, granulating agents, lubricating binders, disintegrating agents and the like. No specific carriers are disclosed and it has proved difficult to find good pharmaceutical carriers.
Efforts to find a good carrier for rioprostil are disclosed in three recently published German patent applications assigned to BAYER A G, namely; No. DE 3304-864-A teaches a stable adsorbate of rioprostil on dextran; No. DE 3304-880-A teaches a stable adsorbate of rioprostil on pregelatinized starch; and No. DE 3304-867-A teaches a stable adsorbate of rioprostil on crospovidone, which is a cross-linked polyvinylpyrrolidone.
BAYER patent application No. DE 3304-867-A states:
The rioprostil crospovidone is a different material than the rioprostil/PVP complex of the present invention, which utilizes a non-cross-linked PVP, and also exists not as a mere physical mixture, but as a complex held together by chemical bonds with its own unique physical/chemical properties. Note that the cross-linked PVP referred to above is relatively insoluble in water, while the PVP used in the present invention is relatively soluble in water.
While PVP has often been used as the carrier for various prostaglandins, it has not been known in the form of a prostaglandin-PVP complex, as in the present invention.